This invention relates generally to the targeted therapeutic delivery of vitamin D compounds and, in particular, delivery to bone and tumor tissue.
Too often the practicing clinician is faced with an unresolvable dilemma. To effectively achieve therapy against a disease, it becomes necessary to balance the devastation wrought by the illness against the noxious effects conferred by the drugs used to treat it. Although therapy should represent a complete tolerance to the dose regimen, in absolute terms it frequently delineates a compromise position, thereby effecting only an “acceptable” level of treatment.
In the absence of preventive measures to combat the onset of disease, the next ideal alternative is to design a drug that specifically recognizes the origin of the disorder and then corrects it. This so-called “magic bullet” or site-specific drug delivery concept is not a new concept. Such a concept is directed to linking the action of drugs to specific receptor-mediated events. These concepts still serve as a primary foundation for the continuing development of drugs and antibodies.
Chemical modification of a drug, in some cases enhances its target organ specificity. For example, brain-targeted delivery systems based on the dihydropyridine-pyridinium salt redox interconversion have been developed for compounds such as estradiol and ethinylestradiol. Brewster et al., 31 J. Med. Chem. (1988) 244. Covalent coupling of some sugars to drugs can enhance their uptake by the liver. Ponpinom et al., in Receptor Mediated Targeting of Drugs, (Gregoriadis et al, eds.) NATO ASI series, Plenum Press, New York, 1983, p. 53.
In most cases, however, a specific carrier is needed that is designed for transport and delivery of the drug to its target tissue. In such cases, the distribution characteristics of the drug itself are irrelevant, since the carrier characteristics determine whether the drug is delivered to the target cells. However, once delivered to the target cells, it still will be necessary to consider the distribution of the drug at its intracellular effect site.
A number of particles have been proposed as drug carrier systems. Recent interest has focused on monoclonal antibodies and colloidal delivery systems such as liposomes and polymeric microspheres. See, e.g., Davis et al. in Site-Specific Drug Delivery, (Tomlinson et al. eds.), John Wiley, New York, 1986, p. 93.
Soluble molecules have also been proposed as drug carriers, including DNA, lectins, poly-L-lysine, virosomes, insulin, dextran, HCG, dipeptides and even cellular systems such as erythrocytes and fibroblasts. See, e.g., Poznansky et al., 36 Pharmacol. Rev. (1984) 277. Still others have suggested and attempted to use lipoproteins as drug carriers, especially low-density lipoproteins. See, e.g., Counsell et al., 25 J. Med. Chem. (1982) 1115.
Obviously, the need for site-specific drug delivery is highest in pathological conditions such as cancer and severe viral infections. Side effects of the drugs utilized in the treatment of neoplastic diseases often are quite severe. Other fast-growing tissues such a bone marrow and gastrointestinal border cells are affected by the antineoplastic drug, and therapy will often have to be stopped.
The need for site-specific drug delivery is also high in bone conditions, particularly osteoporosis. With the recognition that osteoporosis occurs to some extent in all postmenopausal women, the site-specific delivery of bone agents to the mineralized bone matrix has been proposed. Certain agents are known for their bone-seeking characteristics or bone affinity, and the linkage of such bone-seeking agents to enzymes, steroids, or hormones to provide a bone-specific drug delivery agent has been advanced. For example, it has been proposed to join a bone-seeking agent, such as tetracycline, to a carbonic anhydrase inhibitor through a bridging agent to provide compounds for the treatment of or prophylaxis of degenerative bone diseases. See, European Patent Application No. 201,057.
Further, it has been taught to link a hormone, e.g., calcitonin or insulin-like growth factor, to an amino methylene bisphosphonic acid. See, Japanese Patent Application No. 2104-593A. U.S. Pat. No. 5,183,815 discloses that the linkage of a steroid to an alkyl bisphosphonic acid can exhibit a localized therapeutic effect on bone. European Patent Application No. 0 512 844 A1 discloses linkage of a bone growth factor, such as transforming growth factor-beta, to bone-targeting molecules such as tetracycline, calcitonin, bisphosphonates, polyaspartic acid, polyglutamic acid, aminophosphosugars, or estrogens to provide a local bone-augmenting formation agent.
Vitamin D has long been established as having an important biologic role in bone and mineral metabolism. It is well known that vitamin D plays a critical role in stimulating calcium absorption and regulating calcium metabolism. The discovery of active forms of vitamin D, (M. F. Holick et al., 68 Proc. Natl. Acad. Sci. USA, 803-804 (1971); G. Jones et al., 14 Biochemistry, 1250-1256 (1975) and active vitamin D analogs (M. F. Holick et al., Science 180, 190-191 (1973); H. Y. Lam et al., Science 186, 1038-1040 (1 974)), caused much excitement and speculation about the usefulness of these vitamin D compounds in the treatment of bone depletive disorders.
Animal studies examining the effects of these active vitamin D compounds suggested that such agents would be useful in restoring calcium balance. Further, an early clinical study indicated that administration of 0.5 μg/day of 1α, 25-dihydroxyvitamin D3, the hormonally active form of vitamin D3, to a group of postmenopausal women improved the intestinal calcium absorption as well as the calcium balance in the women. On this basis, U.S. Pat. No. 4,225,596 (“596 Patent”) described and claimed the use of 1α,25-dihydroxyvitamin D3 for increasing calcium absorption and retention. Such use also was claimed in the same patent for 1,25-dihydroxyvitamin D2, and 1α-hydroxyvitamin D2, which compounds, the patent teaches, are “eminently suitable and readily substitutable for the 1,25 dihydroxycholecalciferol [1α,25-dihydroxyvitamin D3].”
The best indicator of the efficacy of vitamin D compounds in the prevention or treatment of depletive bone disorders, however, is bone itself rather than calcium absorption or calcium balance. More recent clinical data indicates that, at the dosage ranges taught in the '596 Patent, 1α,25-dihydroxy-vitamin D3 has, at best, modest efficacy in preventing or restoring loss of bone mass or bone mineral content (S. M. Ott and C. H. Chesnut, Ann. Int. Med. 110:267-274 (1989); J. C. Gallagher et al., Ann. Int. Med. 113:649-655 (1990); J. Aloia et al., Amer. J. Med. 84:401-408 (1988)).
These clinical studies with 1α,25-dihydroxyvitamin D3, and another conducted with 1α-hydroxyvitamin D3 (M. Shiraki et al., Endocrinol. Japan 32, 305-315 (1 985)), indicate that the capacity of these two vitamin D compounds to restore lost bone mass or bone mineral content is dose-related. These studies also indicate, however, that at the dosage ranges required for either of the compounds to be truly effective, toxicity in the form of hypercalcemia and hypercalciuria becomes a major problem. Specifically, attempts to increase the amount of 1α,25-dihydroxyvitamin D3 above 0.5 μg/day have frequently resulted in toxicity. At dosage levels below 0.5 μg/day, no effects are observed on bone mass or mineral content. (See G. F. Jensen et al., Clin. Endocrinol. 16, 515-524 (1 982); C. Christiansen et al., Eur. J. Clin. Invest. 11, 305-309 (1981)). Two μg/day of 1α-hydroxyvitamin D3 was found to have efficacy in increasing bone mass in patients exhibiting senile osteoporosis (O. H. Sorensen et al., Clin. Endocrinol. 7, 169S-175S (1977)). Data from clinical studies in Japan, a population that has low calcium intake, indicate that efficacy is found with 1α-hydroxyvitamin D3 when administered at 1 μg/day (M. Shiraki et al., Endocrinol. Japan. 32:305-315 (1985); H. Orimo et al., Bone and Mineral 3, 47-52 (1987)). At 2 μg/day, however, toxicity with 1α-hydroxy-vitamin D3 occurs in approximately 67 percent of the patients, and at 1 μg/day, this percentage is approximately 20 percent.
More recently, other roles for vitamin D have come to light. Specific nuclear receptors for 1α, 25-dihydroxyvitamin D3 have been found in cells from diverse organs not involved in calcium homeostasis. For example, Miller et al., 52 Cancer Res. (1992) 515-520, have demonstrated biologically active, specific receptors for 1α,25-dihydroxyvitamin D3 in the human prostatic carcinoma cell line, LNCaP.
More specifically, it has been reported that certain vitamin D compounds and analogs are potent inhibitors of malignant cell proliferation and inducers/stimulators of cell differentiation. For example, U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1α-hydroxyvitamin D compounds, specifically 1α,25-dihydroxyvitamin D3 and 1α-hydroxyvitamin D3, possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia. In another example, Skowronski et al., 136 Endocrinology (1 995) 20-26, have reported antiproliferative and differentiating actions of 1α,25-dihydroxyvitamin D3 and other vitamin D3 analogs on prostate cancer cell lines.
Previous proliferation studies, such as those cited above, focused exclusively on vitamin D3 compounds. Even though such compounds may indeed be highly effective in differentiating malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism. At the levels required in vivo for effective use as antileukemic agents, these same compounds can induce markedly elevated and potentially dangerous blood calcium levels, by virtue of their inherent calcemic activity. That is, the clinical use of 1α,25-dihydroxyvitamin D3 and other vitamin D3 analogs as anticancer agents is precluded, or severely limited, by the risk of hypercalcemia. This indicates a need for compounds with greater specific activity and selectivity of action, i.e., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity than therapeutic amounts of the known compounds or analogs of vitamin D.
Virtually nothing in the art proposes materials or methods for the targeted delivery of vitamin D compounds to specific target tissue, e.g., bone or malignancy sites, such as prostatic cancer cells.